Human lymphocyte function-associated antigen (LFA)-1 is a heterodimeric lymphocyte surface glycoprotein and a member of the integrin family. It has a broad distribution and is present on cells of the lymphocytic, granulocytic, and monocyte series. LFA-1 functions primarily as an adhesion molecule, mediating cell-cell interactions in inflammation playing an important role in cytotoxic T lymphocyte (CTL)-mediated cell lysis by enabling the formation of conjugates between CTLs and their target cells.
Animal and human studies have confirmed a role for adhesion molecules in a variety of pathological processes, including chronic viral hepatitis, transplant rejection, septic shock, immunologically-mediated lung and kidney disease and other autoimmune disorders. Studies suggest that the expression of these adhesion molecules may be a useful marker for active inflammation under certain conditions and that abrogation of endothelial adhesion by interfering with such molecules may inhibit tissue injury.
The role of adhesion molecules in HIV disease has been demonstrated. Adhesion molecules are involved in different stages of HIV-1 infection and affect HIV-1 neutralization by virus-specific antibodies. In cell-to-cell interactions, the presence of LFA-1 was found to be crucial for virus-mediated syncytium formation. In cell-free viral transmission, LFA-1 particles incorporated into the virion retain their biological functions and have been shown to increase virus-cell interaction, enhance virus infectivity, and extend the host cell range of the virus. In addition, it has been reported that neutralizing activities of both HIV+ plasma and human anti-gp120 monoclonal antibodies are enhanced by an anti-LFA-1 monoclonal antibody capable of blocking LFA-1 functions.
Adhesion molecules are expressed on CD8+ cytotoxic-T lymphocytes (CTLs) prevalent in individuals with HIV infection. Given their role in CTL-mediated lysis of target cells, LFA-1 may also be involved in the progressive depletion of CD4+ T cell counts in HIV-infected patients. In addition to the cytopathic effects of viral products and the direct killing by HIV-specific CTLs, indirect mechanisms have been proposed to explain T-cell depletion. One particular hypothesis may be the killing of uninfected CD4+ T cells. Several studies have identified a population of non-HLA-restricted CTLs which lyse uninfected activated CD4+ lymphocytes. This population is present only in HIV seropositive individuals, but not in seronegative controls, and its activity has been shown to coincide with a drop in CD4+ lymphocyte numbers in vivo in some individuals.
Several mouse hybridoma lines producing monoclonal antibodies reactive with LFA-1 have been studied. Purportedly, anti-LFA-1 monoclonal antibodies reversibly inhibited CTL killing by slowing the initial rate of cytolysis and by interfering with conjugate formation between effector and target cells.